Man and other vertebrates have evolved innate and adaptive host response mechanisms to clear viral infections and provide permanent resistance thereafter. Among the most important weapons against these pathogens are cytotoxic lymphocytes that can lyse virus-infected cells and secrete anti-viral cytokines such as interferon (IFN)g. These include natural killer (NK) cells and T cells expressing either gamma sigma or alpha beta T cell receptors (TCR). My laboratory originally showed that NK cells in mice become activated during infections and clear viruses such as murine cytomegalovirus (MCMV), an important model for human CMV. We report here progress showing that gammas T cells become activated and control infections with vaccinia virus (VV), which is used for human small pox vaccination. We also describe the new phenomenon of heterologous T cell-dependent natural immunity, whereby subpopulations of memory T cells specific for one virus become activated and alter the pathogenesis of putatively unrelated viruses early in infection. The functions of these cytotoxic lymphocytes are regulated by membrane receptor molecules. "NK receptors" (NKR) are on most NK cells and some T cells, and we report here that they are expressed on many virus-induced gamma sigma T cells and on distinct subpopulations of conventional virus-specific alphabeta T cells of the memory phenotype. Here, we propose to continue our integrated studies examining innate and adaptive immunity to viral infections and the contributions of NXR to the different classes of cytotoxic lymphocytes that regulate these infections. We will (1) examine the role of NKR on alphabeta T cell repertoire development during viral infection, (2) examine the activation and antiviral activity of gamma T cells during VV infection, (3) evaluate the role of negative signalling by NKR in the control of infections by T cells and NK cells, and (4) examine redundancies, synergisms, and antagonisms of NK, gamma sigma T, and memory alphabeta T cell responses to viruses. This work should clarify how these effector systems act and interact to rid the host of infectious agents and tumors.